The category B Biodefense infectious agents enterotoxigenic E. coli and Vibrio cholera cause secretory diarrhea. These water and food-borne pathogens release enterotoxins that activate signaling cascades which increase chloride flux through the cystic fibrosis transmembrane regulator (CFTR), a cyclic nucleotide gated chloride channel expressed in epithelial cells of the intestine. The augmented chloride flux leads to passive sodium flux with water following, thereby causing secretory diarrhea. Compounds that inhibit CFTR constitute novel treatments for secretory diarrhea. Our collaborator Dr. Alan Verkman recently discovered compounds capable of inhibiting CFTR with nanomolar potency, and this application aims to advance those compounds through clinical development. Together with Dr. Verkman's group at UCSF and Dr. David Taylor's group at Johns Hopkins, we have planned a comprehensive drug development program to test a CFTR inhibitor as an antidiarrheal. The program includes lead prioritization using in vitro activity assessments, predictive pharmacology and toxicology, as well as in vivo efficacy and non-GLP pharmacology and toxicology assessment. Following that, manufacturing of pre-clinical supplies and GLP animal testing to complete an IND will be performed under our direction through the use of service providers. After protocol and IND approval, phase I testing to assess safety, tolerability and pharmacokinetics will be performed by Dr. Taylor at Johns Hopkins. The program will conclude with a phase II clinical trial where efficacy will be tested in healthy volunteers who will undergo challenge with diarrhea-inducing enterotoxigenic E. coli. At the program's conclusion, we will have a drug product which has undergone clinical proof of principle testing, ready for multi-center pivotal clinical trials.